Morphine is typically used in therapy in the form of morphine sulfate or a hydrate thereof.
Morphine sulfate is an opioid compound with specific affinity for the receptors .mu., .delta. and .kappa.. The principal actions of therapeutic value are analgesia and sedation. The precise mechanism of the analgesic action is unknown. Specific opioid receptors have been located in the brain and the spinal cord and are likely to play a role in the expression of analgesic effects.
Following oral administration of a given dose of morphine, the amount eventually absorbed is essentially the same irrespective of the formulation. Morphine is subject to presystemic elimination (metabolism in the gut wall and liver) and therefore only 40% of the administered dose reaches systemic circulation. Virtually all morphine is converted to glucuronide metabolites; morphine-3-glucuronide (present in highest concentrations but inactive) and morphine-6-glucuronide. A large body of evidence from animal experiments show that morphine-6-glucuronide is a potent .mu.-opioid agonist, with the potential to contribute to morphine's analgesic response.
Morphine undergoes significant hepatic first pass metabolism to form morphine-6-glucuronide. About 90% of a dose of morphine is excreted in the urine mainly as either this conjugate or as morphine-3-glucuronide, while the remainder is excreted in the bile.
Morphine sulphate is generally indicated for the relief of moderate to severe pain most particularly in palliative care, surgery and myocardial infarction. It is intended for use in patients who require repeated dosing with potent opioid analgesic over periods of more than a few days.
Various slow/sustained release morphine formulations have been developed and are described in the literature.
Extended release oral morphine sulphate preparations are considered to be clinically significant as they impart equivalent to superior analgesia with respect to immediate release forms in addition to reducing the likelihood of morphine associated side effects. Morphine sulphate is currently available as a bd dosage form as MS Contin.TM. Tablets (Napp) available as 10 mg, 30 mg, 60 mg, 100 mg and 200 mg active per unit dose. Pain specialists have indicated the requirement for a once daily extended release preparation to avoid break-through pain. Once daily morphine products currently available are those sold under the Trade Marks MST Continus Long and Kapanol.
Apart from achieving sustained release of morphine over extended periods of time, for true therapeutic efficacy a sustained release morphine formulation should achieve therapeutically effective plasma levels of morphine over at least 24 hours coupled with minimum fluctuations in plasma morphine levels.
Morphine-related side effects are a feature of morphine therapy. These side effects include nausea and vomiting, constipation, sedation, confusion and loss of appetite. It has been suggested that the use of modified release morphine formulations, apart from their convenience and their ability to provide continuous analgesia, may also result in a lower incidence and severity of morphine-related side effects (Gourlay, G. K. et al., Pain (1997) 69, 295-302.
U.S. Pat. No. 5,478,577, describes and claims a method for providing effective pain management in humans for a time period of about 24 hours using an opioid analgesic such as morphine in a solid, controlled-release oral dosage form. This dosage form following administration provides a rapid rate of initial rise of the plasma concentration of the opioid, such that peak plasma levels thereof occur from about 2 to about 8 hours and which provides large peak to trough fluctuations in opioid levels even after repeated dosing. Such large peak to trough fluctuations would be expected to maximise attendant morphine-related side effects.
In order to minimise morphine-related side effects, which are a distinct disadvantage and which add to the suffering of those experiencing long-term pain such as cancer patients, what is required is a formulation which exhibits minimal peak to trough fluctuations, namely a substantially flat plasma profile over the dosage period.
A further requirement of a therapeutically effective morphine sustained release formulation is one which maintains a high plasma concentration of morphine over the dosage period.
In case of U.S. Pat. No. 5,478,577 mentioned above peak plasma levels occur from about 2 to about 8 hours after administration.
EP 631,781 discloses morphine formulations having extended controlled release with peak plasma levels in vitro occurring from about 2 to about 6 hours after administration.
Likewise, EP 636,370 discloses morphine-containing sustained release formulations which are described as giving in vivo peak plasma levels relatively early after administration, that is from 1.0 to 6 hours after administration and a W.sub.50 (a parameter defined therein as the width of the plasma profile at 50% C.sub.MAX i.e. the duration over which the plasma concentrations are equal to or greater than 50% of the peak concentration) for morphine of between 4 and 12 hours.
EP 609,961 discloses sustained released compositions which can contain morphine as active ingredient and which can maintain an active ingredient blood level at steady state of at least 75% of maximum blood level (t 0.75 C.sub.max) for approximately 3.5 hours or greater and so that the time at which the active ingredient reaches its maximum concentration (t.sub.max) is 4.5 hours or greater.
WO 94/22431 discloses an oral morphine preparation which achieves a mean serum concentration of morphine of at least 50% of the maximum serum concentration during at least 12 hours after administration of a single dose of the preparation.